The development and initial validation of IgG4-related disease damage index: a consensus report from Chinese IgG4-RD Consortium

Objective To develop and conduct an initial validation of the Damage Index for IgG4-related disease (IgG4-RD DI). Methods A draft of index items for assessing organ damages in patients with IgG4-RD was generated by experts from the Chinese IgG4-RD Consortium (CIC). The preliminary DI was refined using the Delphi method, and a final version was generated by consensus. 40 IgG4-RD cases representing four types of clinical scenarios were then selected, each with two time points of assessment for at least 3 years of follow-up. 48 rheumatologists from 35 hospitals nationwide were invited to evaluate organ damage using the CIC IgG4-RD DI. The intraclass correlation coefficient (ICC) and the Kendall-W coefficient of concordance (KW) were used to assess the inter-rater reliability. The criterion validity of IgG4-RD DI was tested by calculating the sensitivity and specificity of raters. Results IgG4-RD DI is a cumulative index consisting of 14 domains of organ systems, including a total of 39 items. The IgG4-RD DI was capable of distinguishing stable and increased damage across the active disease subgroup and stable disease subgroup. In terms of scores at baseline and later observations by all raters, overall consistency in scores at baseline and later observations by all raters was satisfactory. ICC at the two time points was 0.69 and 0.70, and the KW was 0.74 and 0.73, respectively. In subgroup analysis, ICC and KW in all subgroups were over 0.55 and 0.61, respectively. The analysis of criterion validity showed a good performance with a sensitivity of 0.86 (95% CI 0.82 to 0.88), a specificity of 0.79 (95% CI 0.76 to 0.82) and an area under the curve of 0.88 (95% CI 0.85 to 0.91). Conclusion The IgG4-RD DI is a useful approach to analyse disease outcomes, and it has good operability and credibility. It is anticipated that the DI will become a useful tool for therapeutic trials and studies of prognosis in patients with IgG4-RD.

In Disease duration before treatment, different time units were used for better comprehension.Abbreviations: m, month(s); yr(s), year(s).
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* Case 19: A case scenario sample for IgG4-RD DI Scoring
The patient is a 47-year-old male.He first visited the outpatient clinic for the enlargement of the submaxillary gland and multiple lymph nodes, as well as cough and abdominal discomfort.Physical examination revealed enlarged bilateral submandibular glands, along with cervical, supraclavicular, axillary, and supraglottic lymph nodes.Laboratory tests showed normal complete blood count and blood chemistry tests.His serum IgG level was 40g/L, and serum IgG4 level was 34000mg/L.Computer tomography indicated diffuse enlargement of pancreas and ground glass opacity in both lungs, accompanied with enlarged mediastinal and retroperitoneal lymph nodes.Submandibular gland pathology results supported the diagnosis of IgG4-related disease.Therefore, the patient was diagnosed with IgG4-related disease.On diagnosis, the organ involvement included bilateral submandibular glands, pancreas, lymph node, and lungs.
He received prednisone 40 mg per day and rituximab 1000 mg on day 1 and day 14 for induction remission, and his symptoms were significantly improved.One month after treatment, he was diagnosed with diabetes, which was considered glucocorticoid-related, and his glucocorticoid was tapered within 3 months.The patients reported no discomfort after 6 months of treatment, and the serum IgG4 level decreased to 6800mg/L.However, image examinations still showed persistent pancreas enlargement during follow-up visit.At 3.5 years after treatment, the patient revisited for recurrence of submandibular gland enlargement and new-onset steatorrhea.He had been using insulin to control his blood glucose level.His serum IgG4 level increased to 24000mg/L.Computer tomography indicated enlarged submandibular glands and diffuse enlarged pancreas.
Please evaluate the damage score at 6-month and 3.5-year of treatment according to IgG4-RD DI.

IgG4-RD DI Scoring:
At 6 months, this patient had glucocorticoid-related diabetes with no other persistent organ damage, his IgG4-RD DI score was 1 (treatment-related diabetes).At 3.5 years, this patient still had glucocorticoid-related diabetes, with persistent pancreas enlargement confirmed by imaging.His submandibular gland enlargement had completely recovered at 6 months and remained stable until relapse at 3.5 years, therefore the enlargement of submandibular glands was not considered organ damage.Thus, his IgG4-RD DI score was 2 (treatment-related diabetes and persistent pancreas enlargement confirmed by imaging).
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) damage to other organs not listed above (Abnormal signals in the right temporal and occipital lobes in head MRI) Nervous system: Persistent/residual meninges thickening (Imaging) Mastoid/auris media: Persistent mastoiditis (Imaging), Hearing loss Other: Irreversible damage to other organs not listed above (Abnormal signals in the right temporal and occipital lobes in head MRI) renal parenchyma masses (Imaging) lung fibrosis, impaired lung function Other: Disease-related or treatment-related diabetes mellitus Lung: Persistent lung fibrosis, impaired lung function Pancreas: Pancreatic persistent enlargement (Imaging) Other: Disease-related or treatment-related diabetes mellitus damage to other organs not listed above Lung: Persistent lung fibrosis (Imaging), impaired lung function Retroperitoneum: Persistent retroperitoneal or mediastinal masses Other: Irreversible damage to other organs not listed above, persistent enlargement (Imaging) Liver/biliary tree: Intra-and/or extra-hepatic biliary duct stricture (Imaging) Pancreas: Pancreatic persistent enlargement (Imaging) Liver/biliary tree: Intra-and/or extra-hepatic biliary duct stricture (Imaging) atrophy (Imaging) Liver/biliary tree: Intra-and/or extra-hepatic biliary duct stricture (Imaging), compensated cirrhosis (Child-Pugh grade A) Pancreas: Pancreatic atrophy (Imaging), long-term pancreatic enzyme replacement due to exocrine insufficiency Liver/biliary tree: Intra-and/or extra-hepatic biliary duct stricture (Imaging), compensated cirrhosis (Child-Pugh grade A) Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) tree: Intra-and/or extra-hepatic biliary duct stricture Other: Disease-related or treatment-related diabetes mellitus Pancreas: Pancreatic atrophy (Imaging), Long-term pancreatic enzyme replacement due to exocrine insufficiency Liver/biliary tree: Intra-and/or extra-hepatic biliary duct stricture Other: Disease-related or treatment-related diabetes mellitus -term pancreatic enzyme replacement due to exocrine insufficiency Liver/biliary tree: Intra-and/or extra-hepatic biliary duct stricture Other: Partial or total resection of organs due to IgG4-RD Pancreas: Long-term pancreatic enzyme replacement due to exocrine insufficiency Liver/biliary tree: Intra-and/or extra-hepatic biliary duct stricture Other: Partial or total resection of organs due to IgG4-RD

Table 2 .
The scores of all raters between the damage stable and damage increased group.BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)